Nrf1 and Nrf2 are members of the CNC family of bZIP transcription factors that exhibit structural similarities, and both are expressed in a wide range of tissues. Nrf2 has been shown to coordinate expression of cytoprotective genes in response to oxidative stress and xenobiotic exposures. Nrf1 has also been implicated in this response. The overall goal of our research is to understand the cytoprotective functions mediated by the Nrf1 pathway. We have demonstrated the Nrf1 and Nrf2 are functionally redundant during early development and oxidative stress response. However, Nrf2 does not rescue Nrf1 mutants during late stages of development suggesting there are additional functions unique to Nrf1. Recent investigations have demonstrated the importance of Nrf1 in survival of hepatocytes. Using ES-cell chimeras, Nrf1-deficient cells contributed to fetal, but not adult, liver cells. Inactivation of Nrf1 in the adult liver results in enhanced hepatic apoptosis, and development of steatohepatitis and cancer. We have also demonstrated that the Nrf1 is regulated differently than Nrf2. Our studies suggest that Nrf1 is localized to the endoplasmic reticulum membrane, but mechanisms regulating its release and translocation to the nucleus are not known. We hypothesize that loss of Nrf1 function impairs stress response that promotes apoptosis inciting a vicious cycle involving inflammation, induction of further liver damage ultimately leading to cancer. In the current study, we will extend our studies on Nrf1 in cellular stress response. The goals within this context will be pursued by determining the mechanism of apoptosis and the role of apoptosis in liver damage in the Nrf1 knockouts, delineating stress response pathway regulated by Nrf1 that are important in maintaining cellular homeostasis and survival, and determining mechanisms that regulate Nrf1 function. The studies outlined should advance our understanding of the physiologic role of Nrf1 against cellular stress and provide insights to the pathogenic mechanisms at play in Nrf1 liver knockouts that may be relevant to cancer and degenerative diseases. PUBLIC HEALTH RELEVANCE. Cellular stress is initiated by diverse challenges including reactive oxygen molecules, environmental agents, protein misfolding and etc. Cellular stress leads to damage and dysfunction, and activates pathways leading to cell proliferation or death. Abnormal responses to cellular stress have been implicated in various diseases including cancer and degenerative diseases. We will study the role of Nrf1 protein that regulates cytoprotective mechanisms in the cell. Understanding basic information regarding the role Nrf1 in stress response should provide information relevant to the pathophysiology and therapy of a broad range of human diseases.